In this new paper, Spencer Brown MD et. al. performs four pre-clinical experiments to elucidate the acute biological effects of the Ultrashape device for non-invasive fat cell disruption. Brown’s five co-authors are Ultrashape employees. In general, the presented work appears to be careful and the results accurate. Unlike the previously reviewed Zeltiq pre-clinical study, however, several important pre-clinical experiments were not performed, so we still do not know how the acute biological effects of the Ultrashape device are related to ultimate clinical outcomes.

In the first two experiments, the authors characterize the energy delivery of the UltraShape probe in water, which is a standard method for characterizing ultrasound energy fields. Brown shows that the device focuses the ultrasound energy in a volume that has a diameter of about 8mm, and a depth that ranges from about 5mm to about 25mm from the probe. Brown shows that the energy density (power per cm2) at the probe-water interface is very small, as desired. Further, the authors showed that the ultrasonic energy created air bubbles in the focal region, consistent with a non-thermal cavitation effect. Quantitative measures of ultrasonic power density were performed at 0mm and 14mm depth, and showed an absence of “hot spots.” An improvement to the study would have included power density measurements at 1.5-2mm (approximately the depth of the dermal-fat junction) and 25mm (to characterize the extent of the ultrasonic energy transmission).

In the third experiment, the UltraShape probe was characterized in a gel phantom intended to simulate the ultrasound transmission properties of skin and fat. In this case the focal volume was 9mm in diameter (slightly less focused than in water) and extended about 18mm in depth (the distance from the surface was not reported, but appears to extend from about 4mm to 22mm from the probe according to the figure). Again, bubbles were seen in the focal region in this model, consistent with a non-thermal cavitation effect.

In the fourth experiment, porcine skin was treated and then immediately evaluated with both frozen sections and histologically stained sections. Untreated control skin was also evaluated to ensure that results were not due to processing artifact. Importantly, no effect on skin color or skin appearance was seen on the animals receiving this treatment, and histology showed that the dermis and epidermis appeared to be completely unaffected by the treatment. The subcutaneous fat, however, showed evidence of tissue injury in both the frozen sections and the histology. Histological staining for LDH activity using NTBC (elevated levels of LDH indicate tissue breakdown) demonstrated a layer of adipocyte cell breakdown extending from about 15mm to 25mm of tissue depth. In the treated tissue, but not the control tissue, frozen sections and two other histological stains (H&E and Masson’s Trichrome) indicated a “defined area of tissue destruction” extending from approximately 8mm to 18mm of tissue depth. This region showed clear disruption of fat cells, while connective tissue, blood vessels and nerves remained intact. No evidence of any thermal damage was seen in any treated tissue, again “consistent with initial cavitation followed by the mechanical destruction of cells.” The authors state that fourteen animals were treated in this study, and the results were “consistent over time” despite the use of “multiple devices, [and] multiple transducers [by] numerous users.” No quantification of subject-to-subject variability was provided. For example, the authors should have measured the zone of tissue damage in each animal, and presented the results as averages with 95% confidence intervals.

So far, the results are promising, with clear evidence of non-invasive damage to subcutaneous fat and no apparent impact to the dermis. Unfortunately, the analysis stops there. For example, it is clear from the presented images that not all fat cells in the treated region were disrupted, but the authors do not quantify the percentage of the treatment volume that was disrupted. Further, the response of the animal to this treatment was not studied. Biopsies of treated and control areas were not performed at meaningful time durations subsequent to treatment (such a 1 day, 1 week, 1 month and 3 months post-treatment). Unlike the recent Zeltiq study, we have no idea how the skin and subcutaneous fat respond to these injuries. Does inflammation occur? While no changes to the histology of the dermis were seen immediately post-treatment, could an inflammatory response occur over time? Are non-viable cells removed or replaced? Does this treatment cause meaningful changes in fat thickness compared to control volumes over time, and if so, when do these changes occur? Lastly, blood lipid profiles were not analyzed in this study. We cannot know if release of lipids from the disrupted adipocytes has any systemic effect, either on blood lipids or the liver.

The authors state that these study “observations do not directly lead to predict clinical results,” and they recommend further clinical evaluation. However, the real need is for further pre-clinical evaluation. Perhaps this partly explains why this device, widely available in Europe and Canada, is not yet cleared by the FDA.